Evaluation of intrarenal oxygenation in iodinated contrast-induced acute kidney injury-susceptible rats by blood oxygen level-dependent magnetic resonance imaging

Abstract

Objectives: The objectives of this study were to evaluate differences in intrarenal oxygenation as assessed by blood oxygen level-dependent (BOLD) magnetic resonance imaging in contrast-induced acute kidney injury (CIAKI)-susceptible rats when using 4 contrast media with different physicochemical properties and to demonstrate the feasibility of acquiring urinary neutrophil gelatinase-associated lipocalin (NGAL) levels as a marker of CIAKI in this model.

Materials and methods: Our institutional animal care and use committee approved the study. Sixty-six Sprague-Dawley rats were divided into CIAKI-susceptible groups (received nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester [10 mg/kg] and cycloxygenase inhibitor indomethacin [10mg/kg]) and control groups (received saline instead). One of the 4 iodinated contrast agents (iothalamate, iohexol, ioxaglate, or iodixanol) was then administered (1600-mg organic iodine per kilogram of body weight). Multiple blood oxygen level-dependent magnetic resonance images were acquired on a Siemens 3.0-T scanner using a multiple gradient recalled echo sequence at baseline, after N-nitro-L-arginine methyl ester (or saline), indomethacin (or saline), and iodinated contrast agent (or placebo). R2* (R2*=1/T2*) maps were generated inline on the scanner. A mixed-effects growth curve model with first-order autoregressive variance-covariance was used to analyze the temporal data. Urinary NGAL, a marker of kidney injury (unlike serum creatinine), was measured 4 hours after contrast injection in the 2 subgroups.

Results: Differences in blood oxygen level-dependent magnetic resonance imaging results between the contrast media were observed in all 4 renal regions. However, the inner stripe of the outer medulla (ISOM) showed the most pronounced changes in the CIAKI-susceptible group and R2* increased significantly (P<0.01) over time with all 4 contrast media. In the control groups, only iodixanol showed an increase in R2* (P<0.05) over time. There was an agreement between increases in NGAL and R2* values in ISOM.

Conclusions: In rats susceptible to CIAKI, those receiving contrast media had significant increases in R2* in renal ISOM compared with those receiving placebo. The agreement between NGAL and R2* values in the ISOM suggests that the observed immediate increase in R2* after contrast injection may be the earliest biomarker of renal injury. Further studies are necessary to establish threshold values of R2* associated with acute kidney injury and address the specificity of R2* to renal oxygenation status.

FIGURE 1

Experimental timing diagram. The vertical lines represent the timing of administration of pretreatments and iodinated contrast or placebo. Time periods are shown to scale. blood oxygen level–dependent MRI was performed every 3 minutes for the entire study. The first pretreatment was L-NAME or saline and the second pretreatment was indomethacin or saline. Iodinated contrast refers to one of the 4 agents (iothalamate, ioxaglate, iohexol, or iodixanol) and saline was used as placebo.

FIGURE 2

Representative R2* maps were obtained from one rat in the CIAKI group. Maps are from the same slice position and displayed with the same window and level settings. All the maps were scaled from zero (black) to 80 (blue), representing a range of R2* levels. Larger R2* values correspond to higher levels of hypoxia. The anatomic image of a rat kidney with typical ROI definitions is shown on the far left. Note the progressively increasing R2* values (ie, color changes from yellow and red to green and blue) in the renal outer medulla (ISOM and OSOM) after L-NAME, indomethacin, and iodinated contrast. The cortex did not show change in color, suggesting minimal alteration in oxygenation levels.

FIGURE 3

Summary of the temporal changes in R2* measurements in 4 renal regions. R2* values were normalized to baseline values to allow combining data from different subgroups. The vertical lines show the time of administration of pretreatments and CM agents or saline. Each time course consisted of 35 time points; each point is the average of R2* value from all 6 rats in each subgroup. A, Time courses in 5 subgroups of the CIAKI-susceptible rats. B, Time courses in the 5 subgroups of the control group. As a reference, R2* values at baseline is 21.2 ± 3.4 s^–1 in IM, 37.0 ± 7.1 s^–1 in ISOM, 44.6 ± 4.9 s^–1 in OSOM, and 31.8 ± 3.7 s^–1 in CO in the CIAKI-susceptible group with iodixanol.

FIGURE 4

Summary of individual rat urinary NGAL and BOLD R2* measurements are from 2 groups, the CIAKI-susceptible group with iodixanol (group 11, n = 4) and the placebo group (group 9, n = 3). The group mean values at baseline and after iodixanol/placebo as well as its standard error are displayed on the corresponding sides. Plot A shows individual NGAL measurements. A urine sample was collected at baseline and 4 hours after iodixanol/placebo for NGAL analysis. Urinary NGAL concentrations were normalized to urinary creatinine concentrations. Plot B is the summary of individual BOLD R2* measurements in the renal ISOM from the same rats depicted in plot A. Each data point is the average of R2* readings in the related time period.